Effects Of Butorphanol, Meloxicam And Their Combination On Postoperative Pain, Stress Response And Wound Healing In Dogs Following Ovariohysterectomy

Abstract

Pain, defined as an unpleasant sensory or emotional experience associated with actual or potential tissue damage or described in terms of such damage, is associated with trauma, surgery and disease processes. If pain is not well managed in surgical patients, it can cause stress and impair wound healing in the affected patient. However, the interplay between pain, stress and wound healing in dogs is yet to be elucidated hence the need for this study. This was a two-phased study, where in phase one, a systematic review was carried out to evaluate the type of analgesic drugs and protocols used to manage pain postoperatively in dogs following ovariohysterectomy. Phase two was a randomized controlled clinical studyaimed at evaluating and comparing the effects of butorphanol, meloxicam and their combination on postoperative pain, stress response and wound healing in dogs after ovariohysterectomy. In the systematic review, literature searches in Pub Med, Google Scholar and Science Direct were conducted for peer reviewed articles written in English and published between 1995-2015. The key search words were dogs, ovariohysterectomy, pain and analgesics. This was followed by a manual search of the references within the primary data sources. Inclusion and exclusion of trials into the studywas performed independently by two reviewers. All randomized trials evaluating efficacy of analgesics after ovariohysterectomy in dogs were included. Data on the type of analgesic drugs used, the technique of their administration and the need for rescue analgesia were extracted from the papers. xviii In the clinical trial, forty-eight healthy client-owned dogs scheduled for ovariohysterectomy were randomly assigned to four treatment groups of twelve animals each. The treatment groups were designated as B, M, BM and C. All dogs in the study were sedated using acepromazine at 0.1mg/kg intramuscularly. Ten minutes later, induction was achieved by administering propofol at 5mg/kg intravenously. Anaesthesia was then maintained using isoflurane. Routine ovariohysterectomy was performed on each dog and test analgesics administered at the time of placement of the last skin suture. Dogs in group B received butorphanol at 0.2 mg/kg, group M received meloxicam at 0.2 mg/kg, group BM dogs received butorphanol-meloxicam combination at half the dosage of each drug (0.1 mg/kg butorphanol and 0.1 mg/kg meloxicam), and those in group C, acting as the control, received saline at 0.5ml/10kg body weight. All the test analgesics and placebo were administered subcutaneously. Parameters for pain and stress response were monitored before sedation (baseline) then 1, 2, 4, 6, 12 and 24 hours postoperatively. Pain scores were assessed using the short form Glasgow composite measure pain scale. Sedation scores were assessed using Likert scale based on clinical signs of sedation. Arterial blood pressure, heart rate, respiratory rate and rectal temperature were also assessed. Stress response was assessed by measuring serum cortisol, glucose, neutrophillymphocyte ratio and hematological parameters. Wound healing was assessed on day 1, 2, 3 and 8 day postoperatively using clinical appearance of wounds (swelling, erythema, dehiscence, discharge) and histopathology of wound biopsies (attributes of collagen, epithelialization, neovascularization, fibroblasts, macrophages and neutrophils). In this study, parametric variables were analyzed using ANOVA and student t-test while non-parametric variables were analyzed xix using Kruskal Wallis rank sum test and Mann Whitney test. Statistical significant was set at p<0.05. Thirty-one studies met the inclusion criteria in the systematic review phase of this study. Individual analgesic protocols were used in 83.9% of the studies compared to multimodal drug therapy, which was used in 16.1% of the studies. Opioids were used in 39.0% of studies, NSAIDs in 19.4%, combinations of NSAIDs and opioids in 19.4%, local analgesics in 6.5% and acupuncture in 3.2% of the studies. Drug administration was done using three approaches; pre-operative (64.5%), postoperative (22.6%) as well as combined pre and postoperative approach (12.9%). In 77.4% of the studies, administration of analgesics was done only once while in 12.9% it was done as a 72-hour postoperative course. Twenty four-hour and 48-hour courses of postoperative pain therapy were done in 6.5% and 3.2% of the studies, respectively. About 57% of the dogs in the control groups required rescue analgesia as compared to 21.6% in the single and 11.3% in multimodal drug therapy. The requirement for rescue analgesics was highest in dogs treated using acupuncture (43.8%) and lowest in dogs treated using NSAID-Opioid drug combinations (8.6%). Fewer dogs among those that received pain medication pre- and post-operatively required rescue analgesia as compared to those given analgesics only before or after surgery. More dogs (26.4%) amongthose given analgesics only once postoperatively required rescue analgesia as compared to those that received analgesics daily for 72 hours (4.4%). In the clinical trial, dogs under meloxicam had statistically similar (p=0.68) pain scores compared to those under butorphanol-meloxicam combination but significantly lower pain scores compared to dogs under butorphanol (p=0.01) and those in the control group (p=0.01). Sedation scores were xx significantly (p=0.01) higher for dogs under butorphanol compared to those under meloxicam, the butorphanol-meloxicam combination and those in the control group. Dogs under butorphanol had significantly (p=0.000) lower mean blood pressure (92.0±5.3 mmHg) when compared to those under meloxicam (100.9±2.7 mmHg), butorphanol-meloxicam combination (105.2± 4.4 mmHg) and those in the control group (103.1±3.8 mmHg). There were no significant differences in heart rate, respiratory rate and temperature between the four treatment groups. Mean serum cortisol was statistically similar in the four treatment groups (p=0.36). Dogs under butorphanol-meloxicam combination had significantly lower mean blood glucose (4.7±0.4 mmol/l) compared to that in dogs under butorphanol (5.6±0.6 mmol/l, p=0.008) and those in the control group (5.6±0.7 mmol/l, p=0.01). There were no significant differences in mean neutrophillymphocyte ratio, total leucocyte count, total platelet count, total erythrocyte count, packed cell volume, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and the number of neutrophils, lymphocytes and monocytes in the four treatment groups. Dogs treated using meloxicam had significantly lower scores for clinical appearance of the wounds compared to those under butorphanol (p=0.03) and those in the control group (p=0.02) but statistically similar scores to dogs under butorphanol-meloxicam combination (p=0.39). Dogs in the control group had the highest scores for wound swelling, erythema and dehiscence while those under meloxicam had the lowest scores. Histologically, wound biopsies from dogs under meloxicam and the butorphanol-meloxicam combination had better scores for collagen, xxi epithelialization, neovascularization, fibroblasts, macrophages and neutrophils compared to dogs under butorphanol and those in the control group. The systematic review in this study demonstrated that opioids are the mainstream analgesics used to manage pain in dogs undergoing ovariohysterectomy and that one-time drug administration, preoperative and individual drug therapies are the commonly used techniques. Furthermore, NSAIDs were shown to be more effective in managing postoperative pain in dogs following ovariohysterectomy compared to opioids. Multimodal drug therapies, administration of analgesics before and after surgery, as well as a 72-hour course of pain therapy were practices that provided better outcomes in managing acute postoperative pain in dogs. The clinical trial demonstrated that ovariohysterectomy causes moderate to severe pain lasting for up to 12 hours postoperatively. Meloxicam and butorphanol-meloxicam combination provide an equal level of analgesia without significant adverse effects in dogs following ovariohysterectomy. Butorphanol provides short term analgesia in early postoperative period but is associated with severe sedation and hypotension. Better stress management as indicated by lower cortisol, glucose and neutrophil-lymphocyte ratio was observed in dogs whose pain was treated than in those in the control. Butorphanol-meloxicam combination was the only protocol effective in minimizing stress response in dogs following ovariohysterectomy. Better response to wound healing was indicated by higher scores for wound collagen, epithelialization, neovascularization, fibroblasts and gradually diminishing levels of neutrophil and macrophage scores in pain treated dogs than in those in the control. The quality of wound healing was better in dogs treated with butorphanolmeloxicam combination than individual drugs. xxii It is therefore recommended that veterinarians be informed and encouraged to adopt the practice of administering analgesics both before and after surgery and for at least 72-hours postoperatively while managing pain in dogs after ovariohysterectomy. Further, it is recommended that both opioids and NSAIDs, be made part of routine pain management protocols for dogs undergoing ovariohysterectomy with opioids being administered preoperatively and NSAIDs being administered postoperatively. Butorphanol-meloxicam drug combination as administered in this study is recommended for use in management of acute postoperative pain and stress in dogs undergoing ovariohysterectomy. This study further recommends that a more focused study, using a large number of animal, be conducted inorder to quantify the relationship between pain, stress and wound healing in dogs.